Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Final Activity Report Summary - DUALISTIC HISTOLOGY (Improved diagnosis of cancer patients by novel dualistic histology methods)

Breast cancer is the most prevalent cancer appearing in woman. Every year approximately 4 000 women are diagnosed in Denmark. Pharmacodiagnostics is an emerging discipline with a major potential for improving future clinical care. The principle behind pharmacodiagnostic is the linkage of treatment outcome and molecular changes in the cancer cell. Many breast cancers express the signalling molecule. In oncology pharmacodiagnostics occurred silently in the late 1960s with development of anti-estrogenic treatments with tamoxifen of patients whose tumours express Oestrogen receptor (ER).

Antiestrogens such as tamoxifen target ER. Recently the development of Herceptin (targeting the HER2 oncoprotein in breast cancer) has further demonstrated the close relationship between molecular alteration and clinical response. Within the recent years a lot of research has been performed to further identify molecular changes that could foresee which patients that will benefit from a certain treatment; however, despite a lot of work still only 3 markers of treatment response (ER, HER2 and PgR) has been implemented in the routine diagnostics. The main objectives of the present ToK grant was therefore to use routine histological methods such as Immunohistochemistry (IHC) and Fluorescence in situ hybridisation (FISH) to identify if changes in expression or gene copy numbers of specific intracellular signalling molecules could be used as markers of response to tamoxifen and thereby a new marker to predict patient response to treatment or to forsee patient survival and thereby be used as a diagnostic marker.

To analyse the markers we have mainly used a cohort of 402 ER-positive tamoxifen-treated breast cancer patients. Antibodies used in IHC were all commercial available, whereas the FISH probes were developed by Caroline Witton at Dako as a part of the ToK collaboration. The probes and antibodies were tested in the patient cohort by Tove Kirkegaard at University of Glasgow.

Below is a short summary of the results from the ToK.
1) Patients with high AKT activity were at increased risk of death relative to low risk patients (Kirkegaard et al., 2005; Miami abstract).
2) Overexpression of the ER cofactor, AIB1, was not associated with relapse while treated with tamoxifen. However, AIB1 over expression in patients with HER2-over expressing tumours or tumours expressing one or more of HER1, HER2 or HER3 (HER1-3-positive) was associated with an increased risk of relapse on tamoxifen. AIB1 gene amplification was also tested in the STB-trial. We observed 18 patients (out of 362, 5 %) with AIB1 gene amplification. High AIB1 gene copy number had no effect on overall or disease-free survival (Kirkegaard et al., 2007).
3) Some genomic regions represent hot-spots for molecular alterations underlying initiation and progression of solid tumours. Gene amplifications 11q13 are frequent in breast cancer. This region contains both cyclin D1 (CCND1) and EMSY. CCND1 is implicated in cell cycle progression while EMSY is a BRCA2-associated repressor protein. CCND1 and EMSY gene amplifications were associated with decreased overall survival of ER-positive breast cancers. In line with our hypothesis, CCND1 gene amplifications predicted for poor OS in tamoxifen-treated patients (Submitted, see abstract and San Antonio poster).
4) When gene copy number changes of AKT1-3 was analysed by FISH in 100 of the tamoxifen treated patients, we found 5 (4.8 %) AKT1 deletions and 1 (1 %) amplification. AKT2 was deleted in 19 (21.1 %) carcinomas, whereas no AKT2 amplification was seen. Ten (19.9 %) AKT3 amplification and no deletions were detected. Co-deletion of AKT1 and AKT2 was seen in one tumour whereas six tumour had AKT3 amplification together with deletion of either AKT1 (two cases) or AKT2 (four cases). To our knowledge this is the first study to show gene amplifications and deletions in the three AKT isoforms in breast carcinomas using FISH. The paper is currently been written up and will be submitted as soon as possible.

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